Pyrrolotriazine-5-carboxylate ester inhibitors of EGFR and HER2 protein tyrosine kinases and a novel one-pot synthesis of C-4 subsitituted pyrrole-2,3-dicarboxylate diesters

Pyrrolotriazines with an ester group at C-5 were prepared and evaluated as inhibitors of the EGFR and HER2 receptor tyrosine kinases, validated targets for cancer therapy. The C-5 ester (15) was at least as potent as its C-6 ester analogue (17), an example of a known series of pyrrolotriazine EGRF/HER2 kinase inhibitors that show good biochemical and cellular activity. The C-5 esters were synthesized from pyrrole 2,3-diesters that were made by a new, one-pot procedure. This involved reaction of readily available N-tosyl derivatives of α-amino acid esters or ketones with triphenylphosphine and diethyl acetylenedicarboxylate to form 3-pyrrolines via an intramolecular Wittig olefination. The 3-pyrroline intermediates were not isolated but treated directly with base to eliminate toluenesulfinic acid and generate the pyrrole 2,3-diesters in good yield.Key words: pyrrolotriazine, EGFR, HER2, pyrrole, intramolecular Wittig reaction.

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ChemInform Abstract: Tyrosine Kinase Inhibitors. Part 3. Structure-Activity Relationships for Inhibition of Protein Tyrosine Kinases by Nuclear-Substituted Derivatives of 2,2′-Dithiobis(1-methyl-N-phenyl-1H-indole-3- carboxamide).

ChemInform ◽

10.1002/chin.199450135 ◽

2010 ◽

Vol 25 (50) ◽

pp. no-no

Author(s):

G. W. REWCASTLE ◽

B. D. PALMER ◽

E. M. DOBRUSIN ◽

D. W. FRY ◽

A. J. KRAKER ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Tyrosine Kinases ◽

Kinase Inhibitors ◽

Protein Tyrosine Kinases ◽

Protein Tyrosine ◽

Structure Activity Relationships ◽

Structure Activity ◽

Derivatives Of

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Tyrosine Kinase Inhibitors. 3. Structure-Activity Relationships for Inhibition of Protein Tyrosine Kinases by Nuclear-Substituted Derivatives of 2,2'-Dithiobis(1-methyl-N-phenyl-1H-indole-3-carboxamide)

Journal of Medicinal Chemistry ◽

10.1021/jm00039a016 ◽

1994 ◽

Vol 37 (13) ◽

pp. 2033-2042 ◽

Cited By ~ 22

Author(s):

Gordon W. Rewcastle ◽

Brian D. Palmer ◽

Ellen M. Dobrusin ◽

David W. Fry ◽

Alan J. Kraker ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Tyrosine Kinases ◽

Kinase Inhibitors ◽

Protein Tyrosine Kinases ◽

Protein Tyrosine ◽

Structure Activity Relationships ◽

Structure Activity ◽

Derivatives Of

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Base catalyzed cyclization of substituted esters of hydantoic and thiohydantoic acids

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19860375 ◽

1986 ◽

Vol 51 (2) ◽

pp. 375-390 ◽

Cited By ~ 8

Author(s):

Jaromír Kaválek ◽

Vladimír Macháček ◽

Gabriela Svobodová ◽

Vojeslav Štěrba

Keyword(s):

Phenyl Group ◽

Equilibrium Mixture ◽

Ester Group ◽

Base Catalysis ◽

Ethyl Esters ◽

General Base ◽

Cyclization Rate ◽

Hydrolysis Of ◽

Derivatives Of ◽

Acid Esters

Base catalyzed cyclization rates have been measured of 22 derivatives of hydantoic and thiohydantoic acid esters in water and methanol. The cyclization of methyl and ethyl esters of hydantoic and 5-methylhydantoic acids is accompanied by hydrolysis of the ester group, whereas with the other derivatives the hydrolysis does not take place. Hydrolysis of the cyclization products (hydantoin and thiohydantoin derivatives) is not significant under the kinetic conditions. The cyclization of methyl ester of 5-phenylhydantoic acid in methanol is reversible; the equilibrium mixture contains 30% of the starting ester. In all the cases the cyclization is subject to specific base catalysis; exceptions are esters of 5-phenylthiohydantoic and 5-phenyl-2-methylthiohydantoic acids whose cyclizations are subject to general base catalysis. Substituents always accelerate the cyclization. The 3-substituents have the greatest effects, the cyclization rate being considerably increased with bulk of the substituents; similarly large effect of 5-phenyl group consists mainly in its polar effects on the pre-equilibrium. The cyclization are slower in methanol at the same concentration of the lyate ion: the greatest difference (up to 3 orders of magnitude) is observed with the 5-phenyl derivatives.

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3-(Biphenyl)acrylates by one pot Suzuki cross coupling - Wittig olefination reactions

10.3390/ecsoc-24-08350 ◽

2020 ◽

Author(s):

Thies Thiemann ◽

Areej Hashim ◽

Vijo Poulose

Keyword(s):

Cross Coupling ◽

One Pot ◽

Wittig Olefination ◽

Olefination Reactions

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Role of the ABL tyrosine kinases in the epithelial–mesenchymal transition and the metastatic cascade

Cell Communication and Signaling ◽

10.1186/s12964-021-00739-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Jillian Hattaway Luttman ◽

Ashley Colemon ◽

Benjamin Mayro ◽

Ann Marie Pendergast

Keyword(s):

Solid Tumors ◽

Tyrosine Kinases ◽

Epithelial To Mesenchymal Transition ◽

Kinase Inhibitors ◽

Epithelial Mesenchymal Transition ◽

Therapeutic Effects ◽

Mesenchymal Transition ◽

Metastatic Cascade ◽

Abl Kinases ◽

Treatment Paradigm

AbstractThe ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease.

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Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

Pharmaceuticals ◽

10.3390/ph14070626 ◽

2021 ◽

Vol 14 (7) ◽

pp. 626

Author(s):

Julie Bolcaen ◽

Shankari Nair ◽

Cathryn H. S. Driver ◽

Tebatso M. G. Boshomane ◽

Thomas Ebenhan ◽

...

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Tyrosine Kinases ◽

Radionuclide Therapy ◽

Kinase Inhibitors ◽

Nuclear Imaging ◽

Therapy Resistance ◽

Targeted Radionuclide Therapy ◽

Therapy Strategy ◽

Dismal Prognosis

Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, based on their central role in GB: EGFR, VEGFR, MET, PDGFR, FGFR, Eph receptor and IGF1R. Finally, by way of analyzing structural and physiological characteristics of the TKIs with promising clinical trial results, four small molecule RTKIs were selected based on their potential to become new therapeutic GB radiopharmaceuticals.

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Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP)

International Journal of Molecular Sciences ◽

10.3390/ijms22094417 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4417

Author(s):

Lester J Lambert ◽

Stefan Grotegut ◽

Maria Celeridad ◽

Palak Gosalia ◽

Laurent JS De Backer ◽

...

Keyword(s):

Drug Discovery ◽

High Throughput ◽

Tyrosine Kinases ◽

High Throughput Screening ◽

Kinase Inhibitors ◽

Tyrosine Phosphatase ◽

Protein Tyrosine Phosphatases ◽

Synaptic Function ◽

Label Free ◽

Protein Tyrosine

Many human diseases are the result of abnormal expression or activation of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Not surprisingly, more than 30 tyrosine kinase inhibitors (TKIs) are currently in clinical use and provide unique treatment options for many patients. PTPs on the other hand have long been regarded as “undruggable” and only recently have gained increased attention in drug discovery. Striatal-enriched tyrosine phosphatase (STEP) is a neuron-specific PTP that is overactive in Alzheimer’s disease (AD) and other neurodegenerative and neuropsychiatric disorders, including Parkinson’s disease, schizophrenia, and fragile X syndrome. An emergent model suggests that the increase in STEP activity interferes with synaptic function and contributes to the characteristic cognitive and behavioral deficits present in these diseases. Prior efforts to generate STEP inhibitors with properties that warrant clinical development have largely failed. To identify novel STEP inhibitor scaffolds, we developed a biophysical, label-free high-throughput screening (HTS) platform based on the protein thermal shift (PTS) technology. In contrast to conventional HTS using STEP enzymatic assays, we found the PTS platform highly robust and capable of identifying true hits with confirmed STEP inhibitory activity and selectivity. This new platform promises to greatly advance STEP drug discovery and should be applicable to other PTP targets.

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